DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
1. Claims 1-16, 19-21, 25, and 26 are pending and being examined.
Claim Objections
2. Claim 14 is objected to because of the following informalities: Claim 14 is missing the word “wherein” in the phrase: “The anti-CLL-1 antibody of claim 1, wherein a cytotoxic agent is conjugated…”. Appropriate correction is required.
3. Claim 25 is objected to because of the following informalities: Claim 25 appears to have a typo where “24” should be canceled in the phrase: “The method of claim [[24]] 21, wherein the cancer is expressing CLL-1.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
4. Claim 9 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 9 recites: The anti-CLL-1 antibody of claim 1, wherein the anti-CLL-1 antibody or antigen-binding fragment thereof is…a fully human antibody”.
The specification discloses antibodies comprising the claimed CDR sequences were produced in mice:
Example 1: Preparation of Anti-CLL-1 Antibodies1.1. Monoclonal Antibody Screening by Mouse Immunization
[0265] To prepare anti-CLL-1 antibodies, mouse immunization was performed to screen monoclonal antibodies.
[0266] Briefly, two groups of mice (SJL and Balb/c mice from Charles River Laboratories, Hollister, CA) were immunized by being mixed with human and cynomolgus CLL1 with N-terminus human IgG1 Fc fusion proteins (the mice were produced in-house, and the amino acid sequences of the antigen are shown in Table 4).
[0267] Through ELISA (enzyme-linked immunosorbent assay) screening and FACS (fluorescence-activated cell sorting) analysis, three hybridoma clones were screened as human and cynomolgus CLL1 cross-reactive clones. The three clones were 16C6, 33C2 and 84A2 from immunized Balb/c mice group. Also, all clones positively bound to CLL1 expressing cell lines (U937, HL60) and a cell line overexpressing CLL-1 (cynomolgus CLL1 and human CLL1 are overexpressed in HEK293E cells).
1.2. Monoclonal Antibody Sequencing from Hybridoma Cells and Antibody Chimerization
[0268] To sequence 16C6, 33C2 and 84A2 from immunized Balb/c mice group in Example 1.1., monoclonal antibodies from hybridoma cells were sequenced.
[0269] Briefly, total RNA of murine 16C6, 33C2 and 84A2 was isolated from the hybridoma cells following the technical manual of Trizol reagent (Ambion, Cat. No.: 15596-026). Total RNA was then reverse-transcribed into cDNA through RT-PCR using either isotype-specific anti-sense primers or universal primers. Antibody fragments of VH (variable heavy chain) and VL (variable light chain) were amplified by using the rapid amplification of cDNA ends (RACE) technique. Amplified antibody fragments were cloned into cloning vectors and then were subjected to sequencing. Variable regions and CDRs of the three CLL1 positive clones are shown in Table 5, Table 6 and Table 7. In the tables, HCDR is CDR in heavy chain, LCDR is CDR in light chain.
Tables 5-7 of the specification disclose the instantly claimed CDR SEQ ID NOs derived from murine antibodies.
Claim 9 depends from claim 1 and is limited to anti-CCL-1 antibodies comprising CDR sequences taken from murine antibodies. Therefore, antibodies comprising these CDR sequences are not enabled to be fully human.
Examiner Suggestion: Delete the phrase “fully human antibody” from claim 9.
5. Claims 21, 25, and 26 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for treating cancer expressing CLL-1 in a patient in need thereof, comprising administering to the patient an effective amount of the anti-CLL-1 antibody of claim 1, does not reasonably provide enablement for methods of preventing cancer, and methods of treating cancer that does not express CLL-1. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
Claims 21, 25, and 26 encompass preventing cancer. Claims 21 and 26 encompass targeting and treating cancer that does not express CLL-1.
A search of relevant art does not reveal support for anti-CLL-1 antibodies predictably targeting and treating cancers that lack CLL-1 expression, and preventing cancer.
The specification discloses cancer expressing CLL-1 and the need to target CLL-1 for treatment:
[0004] CLEC12A (C-type lectin domain family 12 member A; also known as C-type lectin-like molecule-1 [CLL-1], CD371, dendritic cell-associated lectin 2 [DCAL2], myeloid inhibitory C-type lectin-like receptor [MICL] and killer cell lectin like receptor-1 [KLRL1]) is a myeloid differentiation antigen expressed on ˜90% of newly diagnosed and relapsed AML. It is a type II transmembrane glycoprotein comprising an extracellular C-terminal lectin domain, transmembrane region, and the N-terminal cytoplasmic tail.
[0005] Monoclonal antibody (mAb)-based therapy has become an important treatment modality for cancer. Leukemia is well suited to this approach because of the accessibility of malignant cells in the blood, bone marrow, spleen, and lymph nodes and the well-defined immunophenotypes of the various lineages and stages of hematopoietic differentiation that permit identification of antigenic targets. Most studies for acute myeloid leukemia (AML) have focused on CD33. However, responses with the unconjugated anti-CD33 mAb lintuzumab have had modest single agent and activity against AML and failed to improve patient outcomes in two randomized trials when combined with conventional chemotherapy.
[0006] There is a need in the art for safe and effective agents that target AML including CLL-1 for the diagnosis and treatment of CLL-1-associated conditions, such as cancer. The invention fulfills that need and provides other benefits.
Example 2.3 and Figure 14 of the instant specification discloses in vitro activity of the anti-CLL-1 antibodies inducing antibody-dependent cell cytotoxicity (ADCC) to kill tumor cells expressing CLL-1.
Examples 4.6 and 4.8, Figures 23, 26, and 27 of the specification demonstrate a bispecific CLL-1 x CD3 antibody is able to treat U937 myeloid leukemia xenograft and HL60-Lu orthotopic AML model, both cancer types expressing CLL-1.
One cannot extrapolate the disclosure of the specification to the scope of the claims because the specification does not provide a working example of the instantly claimed anti-CLL-1 antibodies predictably: (1) targeting and treating cancer that does not express CLL-1; or (2) preventing cancer.
The specification teaches and demonstrates that the anti-CLL-1 antibodies target and bind CLL-1 expressed on the cancer cells to induce ADCC for therapeutic function. Without CLL-1 expression present on the cancer treated in the subject, the anti-CLL-1 antibodies would not be enabled to target cells of the cancer, induce ADCC, and treat the cancer.
The specification lacks the critical steps necessary in presenting some type of predictable response in a population of hosts deemed necessary to prevent cancer. Reasonable guidance with respect to preventing any cancer relies on quantitative analysis from defined populations which have been successfully pre-screened and are predisposed to particular types of cancer or have had cancer. The essential element towards the validation of a preventive therapeutic is the ability to test the drug on subjects monitored in advance of clinical cancer and Iink those results with subsequent histological confirmation of the presence or absence of disease. This irrefutable link between antecedent drug and subsequent knowledge of the prevention of the disease is the essence of a valid preventive agent. All of this underscores the criticality of providing workable examples of prevention which are not disclosed in the specification. A high quantity of experimentation would be required to determine if and what cancers the claimed anti-CLL-1 antibodies could prevent.
Reasonable correlation must exist between the scope of the claims and scope of enablement set forth, and it cannot be reasonably predicted that the claimed anti-CLL-1 antibodies will predictably function to treat cancers not expressing CLL-1 and to prevent cancer as claimed.
Therefore, in view of the state of the art, the quantity of experimentation necessary, the breadth of the claims, lack of guidance in the specification, and the absence of working examples, it would require undue experimentation for one skilled in the art to practice the invention as broadly claimed.
Examiner Suggestion: Amend claim 21 to recite: A method for treating a cancer expressing CLL-1 in a patient in need thereof, the method comprising administering to the patient an effective amount of the anti-CLL-1 antibody of claim 1.
6. Conclusion: No claim is allowed. The closest prior art made of record but not relied upon are US Patent 8,536,310, Abo et al, issued 2013 and US Patent Application Publication 2018/0355044, Jiang et al.
Abo teaches anti-CLL-1 antibodies and methods of treating hematological malignancies expressing CLL-1 in a subject comprising administering to the subject anti-CLL-1 antibodies (abstract; Examples; Figure 3). Abo does not teach the anti-CLL-1 antibodies comprise any of the instantly claimed combination of CDR SEQ ID NOs.
Jiang teaches CLL-1 is expressed on AML cancer cells and cancer stem cells that give rise to additional cancer cells ([2]). Jiang teaches anti-CLL-1 antibodies and administering to them to subjects to treat cancer expressing CLL-1 ([6]; [110]). Jiang does not teach the anti-CLL-1 antibodies comprise any of the instantly claimed combination of CDR SEQ ID NOs.
7. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAURA B GODDARD whose telephone number is (571)272-8788. The examiner can normally be reached Mon-Fri, 7am-3:30pm.
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/Laura B Goddard/Primary Examiner, Art Unit 1642
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